Pharmaceutical composition for preventing cannabis relapse and use thereof

Abstract

A pharmaceutical composition for preventing cannabis relapse and the pharmaceutical and therapeutic use thereof. The pharmaceutical composition comprises pharmaceutical active ingredients naltrexone and risperidone, can be used for treating a patient suffering from cannabis use disorder or any conditions or symptoms related to cannabis use disorder to alleviate the adverse symptoms caused by cannabis addiction, and can be used for preventing cannabis relapse in patients who have recovered from the treatment for cannabis abuse and addiction.

Description

Pharmaceutical composition for preventing marijuana relapse and its application Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a pharmaceutical composition for preventing marijuana relapse and its application, wherein the active pharmaceutical ingredients in the pharmaceutical composition include naltrexone and risperidone. Background Art

[0002] Marijuana, originally derived from extracts of the cannabis plant, is a complex chemical mixture. It was once used clinically as an anesthetic, but was later abandoned due to its addictive potential and significant side effects. It is now primarily traded as a drug. Short-term marijuana use can cause adverse reactions including sedation, congestion, rapid heartbeat, lung irritation and coughing, increased appetite, and decreased blood pressure. Long-term, high-dose marijuana use can cause cognitive and memory impairment, leading to memory loss, anxiety, hallucinations, depression, and even psychosis. This is one of the reasons why marijuana-based sedatives have been abandoned clinically. Studies have shown that marijuana use can trigger hidden mental illnesses and contribute to personality disorders in patients diagnosed with schizophrenia. Other studies have shown that marijuana has significant suppressive effects on the immune system and lung function, potentially inducing respiratory illnesses such as airway inflammation, chronic bronchitis, and pneumonia. It can also increase the risk of invasive testicular cancer.

[0003] Modern pharmacological research indicates that the primary components of cannabis that induce addictive behavior are cannabinoids (exogenous cannabinoids). These can stimulate specific brain regions, thereby stimulating the corresponding reward system and causing changes in brain structure and function. Although there are numerous reports on medications for the treatment and prevention of cannabis addiction, these medications are mostly used for detoxification or as adjunctive treatments during the withdrawal phase of addiction. These medications have shown limited efficacy and are rarely used to prevent relapse or treat the adverse symptoms associated with cannabis addiction. Clinically, relapse is generally considered a distinct treatment stage from addiction and withdrawal. After quitting cannabis, drug addicts are highly likely to resume using the substance they abused before quitting. The adverse symptoms associated with addiction cause significant psychological trauma to patients and are a significant factor in inducing relapse. Relapse is not only a common problem among drug users but also a challenge that drug control efforts have long sought to address.

[0004] Therefore, there is an urgent need to develop a drug that can effectively prevent marijuana relapse.

[0005] Summary of the Invention

[0006] Based on this, according to various embodiments of the present application, a pharmaceutical composition for preventing marijuana relapse and its application are provided, and the technical solution is as follows:

[0007] An embodiment of the present application provides a pharmaceutical composition for preventing relapse of marijuana addiction, wherein the active pharmaceutical ingredients of the pharmaceutical composition include naltrexone and risperidone.

[0008] Yet another embodiment of the present application provides the use of the pharmaceutical composition in the preparation of a drug for preventing relapse of marijuana addiction.

[0009] Yet another embodiment of the present application provides the use of the pharmaceutical composition in the preparation of a drug for treating adverse symptoms caused by cannabis addiction.

[0010] Yet another embodiment of the present application provides a method for preventing marijuana relapse, comprising administering a therapeutically effective amount of the pharmaceutical composition to a patient in need thereof.

[0011] Yet another embodiment of the present application provides a method for treating adverse symptoms caused by cannabis addiction, comprising administering a therapeutically effective amount of the pharmaceutical composition to a patient in need.

[0012] The details of one or more embodiments of the present application are set forth in the description below, and other features, objects, and advantages of the application will become apparent from the description and from the claims thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the conventional technology, the following briefly introduces the drawings required for use in the embodiments or the conventional technology descriptions. Obviously, the drawings described below are merely embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on the disclosed drawings without any creative work.

[0014] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the following is a brief introduction to the drawings required for use in the specific implementation methods or the description of the prior art. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.

[0015] FIG1 is a flowchart of a subject experiment for studying the therapeutic effect of a pharmaceutical composition on adverse symptoms caused by marijuana addiction according to one embodiment of the present application. DETAILED DESCRIPTION

[0016] The following, in conjunction with the embodiments and examples, further illustrates the pharmaceutical composition of the present application and its use in preparing a medicament for preventing marijuana relapse or treating adverse symptoms caused by marijuana addiction. It should be understood that these examples are intended to illustrate the present application only and are not intended to limit the scope of the present application. Furthermore, it should be understood that after reading the teachings of this application, those skilled in the art may make various changes or modifications to the present application, and that such equivalent forms also fall within the scope of protection of the appended claims.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application pertains. The terms used herein in the specification of this application are for the purpose of describing specific embodiments only and are not intended to limit this application.

[0018] the term

[0019] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0020] Herein, "preferred", "better", "better", etc. are only used to describe implementation methods or examples with better effects. It should be understood that they do not constitute limitations on the scope of protection of this application.

[0021] In this application, "further", "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be understood as limiting the scope of protection of this application.

[0022] In this application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0023] In this application, when referring to a numerical interval (i.e., a numerical range), unless otherwise specified, the optional numerical distribution within the above numerical interval is considered continuous and includes the two numerical endpoints (i.e., the minimum and maximum values) of the numerical range, as well as every numerical value between the two numerical endpoints. Unless otherwise specified, when a numerical interval refers only to integers within the numerical interval, it includes the two endpoint integers of the numerical range, as well as every integer between the two endpoints. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges subsumed therein.

[0024] In this application, weight can be mass units known in the chemical industry, such as μg, mg, g, and kg.

[0025] As used herein, "subject" and "patient" refer to animals, preferably mammals, more preferably humans, including but not limited to patients with a disease, condition, and / or symptom. The term "mammal" primarily refers to warm-blooded vertebrate mammals, including but not limited to cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice (e.g., rats, mice), pigs, cattle, sheep, horses, humans, etc., preferably primates, and more preferably humans.

[0026] As used herein, "drug" includes any agent, compound, composition, or mixture that provides a physiological and / or pharmacological effect in vivo or in vitro, often with a beneficial effect. The scope of the physiological and / or pharmacological effect produced by the "drug" in vivo is not particularly limited and may have systemic or local effects. The activity of the "drug" is not particularly limited and may be an active substance that interacts with other substances or an inert substance that does not interact.

[0027] As used herein, "pharmaceutically acceptable" refers to those ligands, materials, compositions, and / or dosage forms that are suitable for administration to a patient within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio.

[0028] As used herein, "pharmaceutically acceptable carriers" include buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with the administration of the drug. Each substance must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch, potato starch, and substituted or unsubstituted β-cyclodextrins; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, and maltose. Rice oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other nontoxic compatible substances used in pharmaceutical formulations.

[0029] The present application relates to the use of a pharmaceutical composition in the preparation of a drug for treating marijuana relapse, wherein the active pharmaceutical ingredients in the pharmaceutical composition include naltrexone and risperidone.

[0030] Naltrexone is a non-selective opioid receptor antagonist that completely blocks the pharmacological effects of intravenously injected opioids (such as heroin) by competitively binding to opioid receptors. Risperidone is a selective monoamine antagonist with high affinity for serotonin 5-HT2 receptors and dopamine D2 receptors, and can improve the positive symptoms of schizophrenia.

[0031] The excellent effect of naltrexone in the clinical treatment of patients with opioid addiction has been confirmed, but its effectiveness in treating drug dependence or diseases related to cannabis addiction, especially in preventing cannabis relapse, is still unclear.

[0032] Through experimental research, the present invention discovered that a combination of naltrexone and risperidone has unexpectedly excellent effects in preventing marijuana relapse. The inventors speculate that this is likely related to the mechanism of marijuana addiction relapse.

[0033] The behavioral process of drug addiction is divided into three stages: ① formation; ② withdrawal (stop taking drugs in the living environment) or extinction (stop taking drugs in the training environment. Extinction of specific cues, extinction of environmental cues, extinction of specific + environmental cues); ③ relapse (ignition of cues, small doses of drugs).

[0034] ① Formation: During the development of cannabis addiction, cannabinoids, upon entry into the body, activate cannabinoid type 1 (CB1) receptors within the ventral tegmental area, increasing dopamine levels and inducing its reinforcing properties. Subsequently, compensatory adaptations occur in several non-CB1 receptor systems, including the dopamine receptor system, the 5-HT receptor system, the opioid receptor system, and the GABA receptor system.

[0035] ② Withdrawal: Cessation of chronic cannabis consumption produces a physical withdrawal syndrome. Studies have shown that chronic cannabinoid treatment and subsequent withdrawal lead to decreased neuronal activity in the mesolimbic dopaminergic pathway, contributing to the long-term aversive consequences of drug withdrawal. Other studies have shown that chronic THC exposure alters several intracellular signaling processes, mediating physiological and behavioral changes during withdrawal, such as those in CB1, AC, cAMP, and PKA. Following chronic THC exposure, decreased CB1 receptor expression, synaptic inhibition, and changes in AC, cAMP, and PKA activity have been observed, potentially contributing to withdrawal reactions.

[0036] ③ Relapse: Under baseline conditions, dopamine neurons in the ventral tegmental area are inhibited by activating GABAergic neurons. After the presentation of drug-conditioned cues, dopamine neurons switch to a phasic discharge pattern, thereby activating CB1 receptors on GABAergic neurons, inhibiting GABAergic neurons and thereby disinhibiting dopamine neurons to increase dopamine levels. Cues conditioned to marijuana use can induce drug-seeking responses (i.e., cravings) by triggering phasic dopamine events. Another dopamine-independent mechanism involved in drug-seeking responses involves the interaction of endogenous cannabinoids / glutamate in the corticostriatal junction of the reward system.

[0037] The pharmaceutical composition of the present application may prevent marijuana relapse by regulating the neural pathways involved in relapse behavior.

[0038] In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of a pharmaceutically active ingredient, and the pharmaceutically active ingredient consists of naltrexone and risperidone in a mass ratio of (5-30):1.

[0039] In some embodiments, the pharmaceutical composition comprises the following:

[0040] In some embodiments, a pharmaceutical composition includes: (a) naltrexone; (b) risperidone; and (c) a pharmaceutically acceptable carrier.

[0041] In some embodiments, the carrier is poly(D,L-)lactide.

[0042] In some embodiments, the pharmaceutical composition comprises: (a) naltrexone at a concentration of 0.375 to 0.5 mg / mg; (b) risperidone at a concentration of 0.0375 to 0.05 mg / mg; and (c) poly (D, L-) lactide.

[0043] In some embodiments, the pharmaceutical composition of the present application and pharmaceutically acceptable excipients are prepared together or separately into the form of a clinically acceptable preparation.

[0044] In some embodiments, the formulation includes a liquid formulation and a solid formulation.

[0045] In some embodiments, the formulation is selected from any of the following groups or suitable combinations thereof:

[0046] 1) Tablets, capsules, granules, powders, granules, suspensions or solutions;

[0047] 2) Oral solution, lozenge, injection, suppository, spray, drops or patch.

[0048] In some embodiments, the formulation is in the form of an implant.

[0049] The present application also relates to the use of a pharmaceutical composition containing a therapeutically effective amount of the above-mentioned pharmaceutical active ingredient in the preparation of a drug for preventing relapse of marijuana addiction.

[0050] The definitions of "pharmaceutical composition", "drug", "active pharmaceutical ingredient", etc. are the same as above.

[0051] In some embodiments, the therapeutically effective amount is 0.4-0.6 mg / mg, and can further be selected from 0.4 mg / mg, 0.45 mg / mg, 0.5 mg / mg, 0.55 mg / mg, 0.6 mg / mg, etc.

[0052] In some embodiments, the pharmaceutical composition contains 160 mg to 170 mg of the active pharmaceutical ingredient, and can further be selected from 160 mg, 162 mg, 165 mg, 168 mg, 170 mg, etc.

[0053] According to the above application, the present application also provides a method for preventing marijuana relapse, comprising administering a therapeutically effective amount of the pharmaceutical composition to a patient in need thereof. That is, administering a therapeutically effective amount of the pharmaceutical composition to the patient.

[0054] Administration

[0055] The dosage form and administration mode of the pharmaceutical active ingredient or pharmaceutical composition thereof of the present application are not particularly limited. Representative administration modes include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and topical administration.

[0056] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also include a buffer. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may include opacifying agents, and the release of the active compound or compounds in such compositions may be delayed in a certain portion of the digestive tract. Examples of embedding components that may be used are polymeric substances and waxes. If desired, the active compound may also be microencapsulated with one or more of the above-mentioned excipients.

[0057] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, specifically ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances. For example, a suspension may contain a suspending agent, specifically ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar, or mixtures thereof.

[0058] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0059] Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants, which are prepared by mixing the active ingredient with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as necessary under sterile conditions.

[0060] The drugs of the embodiments of the present invention can be added with various pharmaceutically acceptable excipients to prepare suitable clinical dosage forms, which include but are not limited to the dosage forms described above.

[0061] These pharmaceutically acceptable excipients include, but are not limited to, diluents, wetting agents, adhesives, disintegrants, lubricants, color and flavor regulators, solvents, solubilizers, cosolvents, emulsifiers, antioxidants, metal complexing agents, inert gases, preservatives, local analgesics, pH regulators, isotonic or isotonic regulators, etc. Further: diluents, such as starch, sucrose, cellulose, inorganic salts, etc.; wetting agents, such as water, ethanol, etc.; adhesives, such as starch slurry, dextrin, sugar, cellulose derivatives, gelatin, povidone, polyethylene glycol, etc.; disintegrants, such as starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium cross-linked carboxymethyl cellulose, cross-linked polyvidone, surfactants, Paon disintegrants, etc.; lubricants, such as talc, calcium stearate, magnesium stearate, magnesium lauryl sulfate, micro-powdered silica gel, polyethylene glycol, etc.; color and flavor regulators, such as pigments, spices, sweeteners, Flavoring agents, adhesives, deodorants, etc., such as fuchsin and xylitol; solvents, such as water, oil, ethanol, glycerol, propylene glycol, polyethylene glycol, dimethyl sulfoxide, liquid paraffin, fatty oil, ethyl acetate, etc.; solubilizers, such as Tweens, sorbents, polyoxyethylene fatty alcohol ethers, soaps, sulfates, sulfonates, etc.; cosolvents, such as organic acids (such as citric acid) and their salts, amide and amine compounds, inorganic salts, polyethylene glycol, povidone, glycerol, etc.; emulsifiers, such as spans, Tweens, sorbents, benzyls, glycerol fatty acid esters, high fatty acid salts, sulfates, sulfonates, gum arabic, tragacanth gum, gelatin, pectin, phospholipids, agar, sodium alginate, hydroxide, silicon dioxide, bentonite, etc.; suspending agents, such as glycerol, syrup, gum arabic, tragacanth gum, agar, sodium alginate, cellulose derivatives, povidone, carbopol, polyvinyl alcohol, thixotropic glue, etc.; antioxidants, such as sulfites, metabisulfites, bisulfites, ascorbic acid, gallic acid and its esters, etc.; metal chelating agents, such as disodium edetate, polycarboxylic acid compounds, etc.; inert gases, such as Nitrogen, carbon dioxide, etc.; preservatives, such as parabens, organic acids and their salts (such as sodium benzoate), quaternary ammonium compounds, chlorhexidine acetate, alcohols, phenols and volatile oils; local analgesics, such as benzyl alcohol, chlorobutanol, lidocaine and procaine; pH adjusters, such as hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, acetic acid, sodium hydroxide, sodium bicarbonate, ethylenediamine, meglumine, phosphates, acetates, citric acid, citrate, etc.; isotonic or isotonic adjusters, such as glucose, sodium chloride, sodium citrate, sorbitol and xylitol, etc.It is understandable that the diluents described in the embodiments herein can also be called fillers, and they play the same role in pharmaceutical preparations; the water described in the embodiments herein is water that meets the requirements of the pharmaceutical preparation, such as water for injection, purified water, etc., and the oil is oil for injection; the preservatives described in the embodiments herein can also be called antibacterial agents, which play a role in inhibiting microbial growth and extending the shelf life in the preparation; the lubricants described in the embodiments herein contain flow aids, anti-adhesive agents, etc.; the sugar described in the embodiments herein can be powdered sugar or syrup, and the type of sugar is not limited to glucose; the spices described in the embodiments herein include but are not limited to flavors.

[0062] In some embodiments, the dosage of the pharmaceutical composition is at least 2 units, and each unit of the pharmaceutical composition is 300 mg to 400 mg.

[0063] In some embodiments, the dosage of the pharmaceutical composition is 2 units, and each unit of the pharmaceutical composition is approximately 300 mg to 400 mg. Furthermore, the amount of the pharmaceutical composition per unit is selected from 300 mg, 320 mg, 340 mg, 350 mg, 380 mg, 400 mg, etc. In some embodiments, the frequency of administration is once every three months. Furthermore, considering the differences in the sustained-release effect of the drug in different individuals, the frequency of administration is allowed to fluctuate within a reasonable range, for example, it can be once every 2.5 to 3.5 months.

[0064] In some embodiments, the pharmaceutical composition is administered by implantation. Further, in some embodiments, the implantation site is the abdominal cavity or the arm.

[0065] In some embodiments, the administered dose is at least 2 units of the pharmaceutical composition, and each unit of the pharmaceutical composition is 300 mg to 400 mg.

[0066] In some embodiments, the dosage is 2 units, and each unit of the pharmaceutical composition is about 300 mg to 400 mg. Further, the amount of each unit of the pharmaceutical composition is selected from 300 mg, 320 mg, 340 mg, 350 mg, 380 mg, 400 mg, etc.

[0067] In some embodiments, the subject is a mammal.

[0068] In some embodiments, the subject is a rat or a human.

[0069] In some embodiments, the subject is a LE rat. Further, the administration dose is at least 2 units, each unit of the pharmaceutical composition is 300 mg to 400 mg, and the pharmaceutical composition for administration contains at least 300 mg of naltrexone and at least 30 mg of risperidone.

[0070] To improve the sustained-release effect, the pharmaceutical composition can be prepared as a sustained-release implant.

[0071] In some embodiments, the sustained-release implant is prepared by the steps comprising the following preparation method:

[0072] preparing naltrexone into naltrexone sustained-release microspheres;

[0073] preparing risperidone into risperidone sustained-release microspheres;

[0074] Weighing the required amount of risperidone sustained-release microspheres and naltrexone sustained-release microspheres according to the weight ratio, and adding pharmaceutically acceptable excipients to prepare an implant;

[0075] The mass ratio of naltrexone to risperidone in the implant is (5-30):1.

[0076] In some embodiments, the pharmaceutical composition comprises, by weight percentage, 37.5% to 50% of naltrexone, about 3.75% to 5% of risperidone, and 0.4% to 0.6% of magnesium stearate.

[0077] In some of the embodiments, the preparation method of the sustained-release implant refers to the technical solution in WO2022095203A, and the obtained sustained-release implant has the technical effects consistent with those described in the patent, including: 1) sustained release in vitro for more than 12 weeks; 2) the release conforms to an approximate zero-order mode and the release rate is stable; 3) the release rates of naltrexone sustained-release microspheres and risperidone sustained-release microspheres in vivo are synchronized.

[0078] In some embodiments, the sustained-release implant can still prevent relapse of marijuana addiction three months after implantation.

[0079] The following are some specific examples.

[0080] For experimental parameters not specified in the following specific examples, reference is made to the guidance given in this application document, and reference may also be made to experimental manuals in the art or other experimental methods known in the art, or to the experimental conditions recommended by the manufacturer.

[0081] The raw materials and reagents involved in the following specific examples can be obtained commercially, or can be prepared by those skilled in the art according to known methods.

[0082] 1. Studying the efficacy of pharmaceutical compositions in preventing relapse in marijuana addicts

[0083] Example 1

[0084] This embodiment provides a method for preparing an implant containing a pharmaceutically active ingredient and products prepared by the method, including a naltrexone implant, a risperidone implant, and a naltrexone-risperidone compound implant.

[0085] (1) Preparation of naltrexone implants

[0086] ① Preparation of naltrexone microspheres

[0087] Naltrexone and poly (D, L-) lactide were dissolved in dichloromethane to form the oil phase; water, surfactant polyvinyl alcohol and osmotic pressure regulator sucrose were prepared as the continuous phase solution; the oil phase was added dropwise to the continuous phase solution, thoroughly stirred to homogenize the volatile organic solvent, and then filtered and vacuum dried to obtain dry microspheres.

[0088] ②Material mixing and tableting

[0089] The naltrexone microspheres and magnesium stearate were added into a hopper mixer according to the prescribed amount and mixed evenly. The mixture was then compressed into bare tablets with a specification of 150 mg / tablet.

[0090] ③Coating and drying

[0091] The bare chip is immersed in an ethyl acetate solution of poly (D, L-lactide) and coated, and then dried.

[0092] ④Packaging

[0093] The tablets are placed into vials according to the specified filling volume and sealed with corkscrew caps.

[0094] (2) Preparation of Risperidone Implant

[0095] ① Preparation of risperidone microspheres

[0096] Sodium chloride is dissolved in purified water to form the inner aqueous phase; risperidone and poly (D, L-) lactide are dissolved in dichloromethane to form the oil phase; water, surfactant polyvinyl alcohol and osmotic pressure regulator sodium chloride are prepared into a continuous phase solution; the inner aqueous phase is then added to the oil phase, ultrasonically emulsified to form colostrum, and finally the colostrum is added dropwise to the continuous phase solution, thoroughly stirred to homogenize the volatile organic solvent, filtered and vacuum dried to obtain dry microspheres.

[0097] ②Material mixing and tableting

[0098] The risperidone microspheres and magnesium stearate were added into a hopper mixer according to the prescribed amount and mixed evenly, and tableted to obtain bare tablets with a specification of 15 mg / tablet.

[0099] ③Coating and drying

[0100] The bare chip is immersed in an ethyl acetate solution of poly (D, L-lactide) and coated, and then dried.

[0101] ④Packaging

[0102] The tablets are placed into vials according to the specified filling volume and sealed with corkscrew caps.

[0103] (3) Preparation of naltrexone-risperidone compound implant

[0104] ① Preparation of naltrexone microspheres

[0105] Naltrexone and poly (D, L-) lactide were dissolved in dichloromethane to form the oil phase; water, surfactant polyvinyl alcohol and osmotic pressure regulator sucrose were prepared as the continuous phase solution; the oil phase was added dropwise to the continuous phase solution, thoroughly stirred to homogenize the volatile organic solvent, and then filtered and vacuum dried to obtain dry microspheres.

[0106] ② Sodium chloride was dissolved in purified water to form the inner aqueous phase; risperidone and poly (D, L-) lactide were dissolved in dichloromethane to form the oil phase; water, surfactant polyvinyl alcohol, and osmotic pressure regulator sodium chloride were prepared as the continuous phase solution; the inner aqueous phase was then added to the oil phase and ultrasonically emulsified to form colostrum. Finally, the colostrum was added dropwise to the continuous phase solution, thoroughly stirred to homogenize the volatile organic solvent, and then filtered and vacuum dried to obtain dry microspheres.

[0107] ③Material mixing and tableting

[0108] The above compound microspheres and magnesium stearate were added into a hopper mixer according to the prescribed amount and mixed evenly, and tabletted to obtain bare tablets with the specifications of naltrexone and risperidone being 150 mg and 15 mg per tablet.

[0109] ④Coating and drying

[0110] The bare tablets are soaked and coated with a poly (D, L-lactide) ethyl acetate solution and dried to obtain the naltrexone / risperidone implant tablets, each weighing 300 mg to 400 mg.

[0111] ⑤Packaging

[0112] The tablets are placed into vials according to the specified filling volume and sealed with corkscrew caps.

[0113] The following Examples 2 to 4 study the effects of the pharmaceutical composition of the present application in treating cannabis addiction and preventing relapse.

[0114] Subcutaneous Implantation Method for Sustained-Release Naltrexone: The day before the test article is implanted, shave the hair on both sides of the animal's spine to expose the skin for easy insertion of the naltrexone implant. After the animal is anesthetized with isoflurane, disinfect the local skin with an alcohol cotton ball. Use a scalpel to make an incision approximately 0.5 cm in size. Push the needle forward approximately 3 to 4 cm, moving it side to side to ensure correct entry into the cortex. Then, inject the appropriate dosage of the tablet. Keep the injection site as far away from the spine as possible to avoid pain or injury caused by friction with the tablet due to movement. After suturing, sprinkle anti-inflammatory powder on the wound to ensure wound healing. Thereafter, disinfect the wound surface with iodine tincture daily until it is completely healed. Sterilize the surgical instruments in advance.

[0115] Example 2

[0116] This example studies the anti-relapse effect of the pharmaceutical composition of the present application in the LE rat self-administration model.

[0117] 2.1. Drugs and reagents

[0118] WIN 55,212-2, off-white powder (131543-23-2, Shanghai Yuansi Biao Technology Co., Ltd.);

[0119] Rimonabant, white solid (HY-14137, Shanghai Haoyuan Biopharmaceutical Technology Co., Ltd.);

[0120] The naltrexone-risperidone compound implant prepared in Example 1;

[0121] The naltrexone implant prepared in Example 1;

[0122] The risperidone implant prepared in Example 1;

[0123] The drugs used in the following examples are solutions, and their preparation solvents and dosages are shown in Table 1.

[0124] Table 1

[0125] Experimental animals

[0126] SPF LE rats (Beijing Weitonglihua Experimental Animal Technology Co., Ltd.), weighing 220g-250g, were randomly divided into groups with 10 rats in each group.

[0127] 2.3. Establishment of the Self-Administration Model

[0128] Experimental apparatus: 16-channel rat self-administration system, rat self-administration cages (30.5 cm × 24.1 cm × 21 cm) placed in a ventilated, soundproofed chamber. Each cage's operating surface was equipped with two levers, each with a 2.5 cm diameter, designated as an "active" lever and an "inactive" lever. The levers were 15 cm apart and 5 cm high, each with an LED light above it. A 1 cm diameter white LED cage light was mounted on top of the operating surface. The infusion connection system consisted of an infusion tube, an infusion shaft, and an infusion pump. The infusion tubes were protected by a spring connecting rod to prevent chewing. The cages were computer-controlled.

[0129] Experimental methods

[0130] 2.4.1. Food training

[0131] Starting on the third day of postoperative recovery, the animals were restricted to a 12g diet. From the fourth to sixth day, they were trained to self-feed food pellets at a fixed ratio (FR1) for 1 hour daily to facilitate lever-pressing. Pressing the lever resulted in: (i) the cue light above the lever illuminated for 10 seconds; (ii) a grain appeared in the feeding trough; and (iii) the room light went off for 20 seconds, marking the refractory period (time-out). After the 20-second time-out period, the room light was turned on, and a new round of testing began.

[0132] The other lever is an invalid lever and is not coupled to any continuous event, but is always recorded.

[0133] 2.4.2. Self-administration training

[0134] Seven days after postoperative recovery, self-administration training with WIN55,212-2 (WIN55,212-2 is a cannabis injection solution at a concentration of 12.5 μg / kg / infusion, with rats weighing approximately 200 g) began. Rats were placed in a self-administration training box and connected to a self-administration injection system. Reinforcement training was conducted daily for 2 hours using a fixed-rate 1 (FR1, gradually increasing to FR3). During each self-administration session, the active lever was activated, and the injection system automatically administered drug (intraperitoneally). Each injection was approximately 0.1 mL, lasting 4 to 6 seconds. Each injection was accompanied by a 10-second illumination of the active lever and a 20-second extinguishing of the chamber light. The chamber light was off during a 20-second refractory period, during which no drug was administered if the rat pressed the active lever, but the number of valid lever presses was recorded. Data on the inactive lever was recorded, but no drug was administered. During training, a computer automatically recorded the number of active and inactive lever presses and injections. Food was restricted to 12 g during training. The training success criteria are: the number of marijuana injections in rats gradually increases and stabilizes with the accumulation of training days, and the difference in the number of effective lever presses in the last 3 days stabilizes at around 20%.

[0135] 2.4.3. Self-administration extinction training

[0136] After the self-administration model was established, rats underwent a 2-hour environmental extinction period during each round of extinction training. During the extinction period, only the training environment and lever were presented, without other cues such as lights, pump sounds, or drug injection. A computer automatically recorded the rat's behavioral responses. The rat reached the extinction criterion (i.e., the total number of valid lever presses decreased to 20% of the total number of valid lever presses on the first day of extinction training, or to less than 10).

[0137] 2.4.4. Grouping and Dosing

[0138] After self-administration training and extinction, participants were randomly divided into the naltrexone-risperidone implant group, the naltrexone implant group, and the risperidone implant group based on the number of injections and the number of effective lever presses. The naltrexone-risperidone implant, the naltrexone implant, and the risperidone implant were implanted subcutaneously; the control group and the rimonabant group underwent sham surgery. Postoperative care was provided for three days, and relapse testing was performed starting on the fourth day.

[0139] 2.4.5. Effects of compounds on environmental cue-induced relapse behavior

[0140] Rats in the rimonabant group received a 2 mg / kg rimonabant injection 15 minutes before testing. The control group received saline 15 minutes before testing. The naltrexone / risperidone implant, naltrexone implant, and risperidone implant compound groups received no medication. The animals then underwent a 2-hour relapse test induced by environmental cues consistent with self-administration training, including lever pressing, cage light, and the sound of the syringe pump. However, the syringe pump contained no drug. The number of injections and effective lever presses were recorded by a computer.

[0141] 2.4.6. Extinction training

[0142] The rats were subjected to another 2-h extinction period. During the extinction period, only the spatial environment during self-administration training was presented, without other cues such as lights, pump sounds, and drug injections. The computer automatically recorded the number of behavioral responses of the rats, and extinction continued until the standard was reached.

[0143] 2.4.7. Effects of compounds on drug (WIN55,212-2) combined with environmental cues-induced relapse behavior

[0144] Rats in the rimonabant group received rimonabant injection (2 mg / kg, ip) 15 minutes before testing, at a rate of 2 mg / kg body weight. The control group received saline 15 minutes before testing, and the implant-treated group received no medication. All rats received cannabis (WIN55,212-2 injection 0.3 mg / kg, ip) at a rate of 0.5 mg / kg body weight, followed by a 2-hour relapse test with both drug and environmental cues. The cues were consistent with those used in self-administration training, including lever pressing and the sound of the syringe pump, but the syringe pump contained no drug. The number of injections and effective lever presses were recorded by a computer.

[0145] 2.5 Experimental results

[0146] 2.5.1. Effects of compounds on environmental cue-induced relapse behavior

[0147] In the environmental cue-induced relapse test, the control group exhibited significant relapse behavior, as evidenced by a significant increase in the number of valid lever presses compared to the last extinction period. The naltrexone implant and the combined naltrexone / risperidone implant groups significantly reduced cue-induced relapse behavior, as evidenced by a significant decrease in the number of valid lever presses compared to the control group (Table 2). The reference compound rimonabant did not exhibit a significant inhibitory effect on the relapse test. There were no significant differences among the groups in the number of ineffective lever presses.

[0148] Table 2 Effects of compounds on relapse behavior induced by environmental cues (mean±SD, n=10).

[0149] In Table 2, the data are expressed as Mean ± SEM and analyzed using two-way repeated analysis of variance (compared with the last-ext-Vehicle group: ****p < 0.0001; compared with the Cue-Vehicle group: # p<0.05, ## p<0.01)

[0150] 2.5.2. Effects of compounds on drug-induced relapse behavior induced by combined environmental cues

[0151] In the drug- and environmental-cue-induced relapse test, the control group exhibited significant relapse behavior, as evidenced by a significant increase in the number of lever presses compared to the last extinction period. However, the naltrexone implant and the combined naltrexone / risperidone implant groups significantly reduced cue- and drug-induced relapse behavior, as evidenced by a significant decrease in the number of lever presses compared to the control group (Table 3). The reference compound rimonabant did not exhibit a significant inhibitory effect on the relapse test.

[0152] Table 3 Effects of compounds on drug-induced relapse behavior induced by environmental cues (mean ± SD, n = 10)

[0153] Data are expressed as Mean ± SEM and analyzed by two-way repeated analysis of variance (compared with the re-ext-Vehicle group: *p < 0.05; compared with the Cue + Drug-Vehicle group: #p < 0.05, ##p < 0.01)

[0154] In this example, LE female rats were able to establish stable WIN 55,212-2 self-administration, indicating that the model was successfully established. After self-administration training and extinction were completed, when randomly divided into groups, there were no significant differences between the control group, rimonabant group, naltrexone implant group, risperidone implant group, and naltrexone / risperidone implant group during the training and extinction phases. In the context-induced relapse test, the control group showed significant relapse behavior, while the naltrexone implant and naltrexone / risperidone implant groups significantly reduced cue-induced relapse behavior. In the drug-enhanced context-induced relapse test, the control group showed significant relapse behavior, while the naltrexone implant and naltrexone / risperidone implant groups significantly reduced cue-induced and drug-induced relapse behavior. The positive drug rimonabant did not show a significant inhibitory effect in either relapse test. Therefore, the naltrexone / risperidone implant has a good effect in preventing marijuana relapse, and the naltrexone / risperidone implant is more effective than the single drug.

[0155] Example 3

[0156] This example studies the effect of the pharmaceutical composition of the present application on the formation of self-administration addiction in LE rats.

[0157] 3.1 Grouping and Dosing

[0158] Animals were randomly divided into a model control group, a rimonabant group, a naltrexone / risperidone implant group, a naltrexone implant group, and a risperidone implant group. On the day of intravenous cannulation, the naltrexone / risperidone implant, the naltrexone implant, and the risperidone implant were implanted subcutaneously. The control and rimonabant groups underwent sham surgery. Postoperative care was provided for three days, and addiction training began on the fourth day.

[0159] 3.2 Effects of drugs on the establishment of intravenous self-administration model

[0160] Rats in the control and rimonabant groups were administered the corresponding compound 15 minutes before daily training. Rimonabant (2 mg / kg, ip) was administered to the control group, while the implant-administered group received no medication. Training procedures were the same as those for self-administration training in Example 1. During training, a computer automatically recorded valid and invalid lever presses and the number of injections. Food was restricted to 12 g during training. Training success criteria were: the number of marijuana injections administered to the rats gradually increased and stabilized over the course of training days, with a stable difference of approximately 20% in the number of valid lever presses over the final three days.

[0161] 3.3 Effects of drugs on the extinction of drug-seeking behavior

[0162] After the self-administration model was established, rats underwent a 2-hour environmental extinction period during each round of extinction training. During the extinction period, only the training environment and lever were presented, without other cues such as lights, pump sounds, or drug injection. A computer automatically recorded the rat's behavioral responses. The rat reached the extinction criterion (i.e., the total number of valid lever presses decreased to 20% of the total number of valid lever presses on the first day of extinction training, or to less than 10).

[0163] 3.4 Experimental Results

[0164] The number of effective lever presses during extinction and the number of days until extinction reached stability were recorded. The results are shown in Table 4. As shown in Table 4, administration of rimonabant, naltrexone / risperidone implants, and naltrexone implants significantly inhibited the increase in effective lever presses induced by win55,212-2 (marijuana) addiction. With the exception of the risperidone group, all other treatment groups showed significant differences compared to the control group, with the naltrexone / risperidone implant group demonstrating the strongest inhibitory effect. This suggests that the combined administration of naltrexone and risperidone exhibits a synergistic effect compared to either naltrexone or risperidone alone.

[0165] The order of fastest extinction achievement during the extinction process was the naltrexone / risperidone implant group, the naltrexone / rimonabant equivalent, the risperidone group, and the saline control group. The results showed that each treatment group had a certain inhibitory effect on the extinction process of marijuana addiction, with the combination having the most significant inhibitory effect on extinction, surpassing both the combined treatment group and the single-drug group.

[0166] Table 4 WIN55,212-2 self-administration training and extinction in female LE rats (mean ± SD, n = 10)

[0167] Data are expressed as Mean ± SEM and analyzed by two-way repeated analysis of variance (compared with the Vehicle group: *p < 0.05, **p < 0.01; ***p < 0.001)

[0168] 3.5 Conclusion

[0169] 3.5.1 Effects of Rimonabant at Different Stages of Cannabis Addiction

[0170] Experimental data indicate that rimonabant significantly inhibits the development of marijuana addiction and accelerates extinction during the extinction phase, reducing the number of days to extinction. It also has an inhibitory effect on cue-induced ignition and cue-plus-drug ignition, but the effect is not significant. This suggests that rimonabant may be a preventive measure for marijuana addiction.

[0171] The behavioral process of drug addiction is divided into three stages: ① formation; ② withdrawal (cessation of drug use in the living environment) or extinction (cessation of drug use in the training environment. Extinction of specific cues, extinction of environmental cues, and extinction of specific and environmental cues); and ③ relapse (ignition of cues or small doses of drugs). During the development of marijuana addiction, cannabinoids, after entering the body, activate type 1 cannabinoid (CB1) receptors in the ventral tegmental area, increasing dopamine levels and inducing its reinforcing properties. Subsequently, compensatory adaptations occur in several non-CB1 receptor systems, including the dopamine receptor system, the 5-HT receptor system, the opioid receptor system, and the GABA receptor system. Rimonabant, a type 1 cannabinoid receptor (CB1) inhibitor, was selected as the active drug for the marijuana addiction model. Its blocking effect on CB1 receptors is more effective in the early stages of marijuana addiction. In the relapse stage of marijuana addiction (including cue-induced ignition or cue-plus-drug ignition), the non-CB1 receptor action system plays a very important role. The blocking effect of CB1 receptors is limited, so the effect of rimonabant is relatively limited.

[0172] 3.5.2. Effects of naltrexone and risperidone at different stages of cannabis addiction

[0173] Experimental data show that when the combined naltrexone / risperidone implant is administered in a dose greater than two tablets (i.e., 300mg naltrexone:30mg risperidone), compared to the model group, the combined implant significantly inhibits the development and relapse of marijuana addiction during the development, extinction, cue-induced ignition, and cue-plus-drug ignition phases, and significantly accelerates the stable development of extinction. Therefore, the naltrexone / risperidone implant not only prevents the development of marijuana addiction and accelerates marijuana withdrawal, but also effectively prevents relapse.

[0174] Example 4

[0175] This example studies the effects of different dosages of a pharmaceutical composition on self-administration relapse behavior and the results of blood drug concentrations.

[0176] 4.1. Grouping and Dosing

[0177] The training procedure was the same as in Example 1. After self-administration training and extinction, the animals were randomly divided into a control group and low-, medium-, and high-dose naltrexone / risperidone compound implant groups based on the number of injections and the number of effective lever presses. The low-, medium-, and high-dose naltrexone / risperidone compound implants were implanted subcutaneously; the control group underwent a sham operation. Postoperative care was continued for three days, and the corresponding relapse test was performed starting on the fourth day. Immediately after the end of the experiment on the day of the relapse test, blood was collected from the heart, and plasma was centrifuged to obtain the drug levels of naltrexone, 6-β-naltrexol, risperidone, and 9-OH-risperidone in the plasma.

[0178] 4.2. Effects of drugs on environmental cue-induced relapse behavior

[0179] The control group received saline 15 minutes before the test, while the implant group received no medication. The animals then underwent a 2-hour relapse test induced by environmental cues consistent with self-administration training, including lever pressing, cage light, and the sound of the syringe pump. However, the syringe pump contained no drug. The number of injections and effective lever pressing data were recorded by a computer.

[0180] 4.3. Extinction Training

[0181] The rats were subjected to another 2-h extinction period. During the extinction period, only the spatial environment during self-administration training was presented, without other cues such as lights, pump sounds, and drug injections. The computer automatically recorded the number of behavioral responses of the rats, and extinction continued until the standard was reached.

[0182] 4.4. Effects of drugs on relapse behavior induced by drugs and environmental cues

[0183] The control group received saline 15 minutes before testing, while the implant group received no medication. All rats received WIN55,212-2 (0.3 mg / kg, ip) intraperitoneally and then immediately underwent a 2-hour relapse test with both drug and environmental cues. The cues were consistent with those used in self-administration training, including lever pressing and the sound of a syringe pump, but the syringe pump contained no drug. The number of injections and effective lever pressing data were recorded by a computer.

[0184] 4.5 Experimental results

[0185] The results of the naltrexone-risperidone combination on line-induced ignition and cue-plus-drug ignition at different doses are shown in the table below (Table 4). The experimental results show that as the implanted dose (number of tablets) increases, the blood drug concentration in rats also increases accordingly. Specific results are shown in the table below. In the win55,212-2-induced addiction model, the combination implant had a significant inhibitory effect on line-induced ignition and cue-plus-drug ignition when four and two tablets were implanted. When one tablet was implanted, there was a slight inhibitory effect, but no significant difference. The implant's inhibitory effect on relapse was dose-dependent.

[0186] That is to say, the effect of the combined naltrexone and risperidone implants begins after two tablets, each tablet is 150mg / 15mg, and the sustained-release time is 3 months.

[0187] Table 5 Effects of different drug doses on self-administration relapse behavior and blood drug concentration results (mean ± SD, n = 10)

[0188] In Table 5, the data are expressed as mean ± SEM and analyzed by two-way repeated analysis of variance (compared with the Last-ext-Vehicle group: **p < 0.01, ****p < 0.0001; compared with the Cue-Vehicle group and the Cue + Drug-Vehicle group: #p < 0.05, ##p < 0.01)

[0189] 2. Studying the therapeutic effects of the pharmaceutical composition on adverse symptoms caused by cannabis addiction

[0190] This example is a study on the effectiveness and safety of naltrexone-risperidone implants for post-detoxification relapse prevention treatment of cannabis-dependent patients, and involves the improvement of psychiatric symptoms of naltrexone-risperidone implants for post-detoxification relapse prevention treatment of cannabis-dependent patients.

[0191] 1. Experimental Design

[0192] This study was a single-center, randomized, open-label, placebo-controlled clinical trial initiated by researchers. One hundred patients with cannabis dependence were enrolled.

[0193] Subjects participating in the trial must meet all of the following criteria to enter this study:

[0194] (1) Voluntarily participate in the clinical study; fully understand and be aware of this study and sign the informed consent; be willing to follow and be able to complete all trial procedures;

[0195] (2) Aged ≥18 years when signing the informed consent form;

[0196] (3) meet the DSM-5 diagnostic criteria for cannabis dependence and complete detoxification treatment;

[0197] (4) negative urine marijuana qualitative test (TLC);

[0198] (5) Female subjects have evidence of postmenopausal status, or premenopausal female subjects have a negative serum pregnancy test result before dosing. Eligible subjects (male and female) of childbearing age must agree to use effective contraceptive measures (hormonal or barrier methods or abstinence) with their partners during the trial.

[0199] Participants who meet any of the following criteria will not be included in the trial:

[0200] (1) The researcher determines that participation in this study is not in the interests of the subjects, or any other circumstances prevent the subjects from safely participating in the study;

[0201] (2) Pregnant women, women of childbearing age with a positive pregnancy test, or breastfeeding women, including women of childbearing age who plan to become pregnant during the study period. Note: Women of childbearing age here refer to women of childbearing potential. The following criteria must be met, regardless of their sexual orientation or whether they have undergone tubal ligation: 1) have not undergone hysterectomy or bilateral oophorectomy; or 2) have not undergone natural menopause for more than 12 consecutive months (i.e., have had menstruation at any time in the previous 12 consecutive months);

[0202] (3) Significant liver function abnormalities (such as AST or ALT higher than 2 times the upper limit of normal) or liver failure [including but not limited to: ascites, prolonged prothrombin time, international normalized ratio (INR) ≥ 1.7, esophageal varices disease] or hepatobiliary ultrasound results that have a significant impact on the judgment of the efficacy and safety of the study drug;

[0203] (4) Suffering from clinically uncontrolled active infectious diseases, such as active hepatitis B [positive hepatitis B surface antigen (HBsAg) test and hepatitis B virus (HBV) deoxyribonucleic acid (DNA) copy number >1000IU / ml], active hepatitis C [positive hepatitis C virus antibody and hepatitis C virus (HCV)-ribonucleic acid (RNA) positive], etc.;

[0204] (5) History of congenital bleeding disorders (such as hemophilia) or any active clinically significant bleeding, or platelet function abnormalities, or prothrombin time (PT) exceeding the upper limit of normal by more than 3 seconds in coagulation function tests, or platelet count <50 × 109 / L;

[0205] (6) The researcher judges that the subject has any severe / uncontrollable systemic disease (e.g., respiratory system, circulatory system, digestive system, nervous system, blood system, genitourinary system, endocrine system disease) or mental illness (e.g., major depressive disorder, schizophrenia, bipolar disorder, etc.) or other major disease that the researcher believes will hinder the provision of informed consent, make participation in the study unsafe, complicate the interpretation of the study outcome data, or otherwise affect the achievement of the study objectives;

[0206] (7) may need hospitalization or surgery during the study period, including planned elective surgery or hospitalization that cannot be postponed;

[0207] (8) Currently diagnosed (within one year before randomization / dose) with substance use disorders other than cannabis, such as benzodiazepines Substances such as narcotics, opioids or cocaine;

[0208] (9) Use of anti-relapse drugs (such as naltrexone, risperidone, etc.) within 30 days before randomization / administration;

[0209] (10) Currently receiving treatment for substance use disorders such as opioids and alcohol, or having received opioids within 7 days before randomization / dosing, may require opioid treatment during the study, or have a positive urine opioid, marijuana or other drug test or a positive naloxone provocation test on the day of randomization / dosing;

[0210] (11) Allergy to the study drug or its excipients (polylactic acid, magnesium stearate), or local anesthetics;

[0211] (12) Currently participating in any study of research drugs or devices, or having used any research drugs or devices within 30 days before randomization / dosing;

[0212] (13) Skin infection or systemic skin disease at the implantation site, which is judged to affect the efficacy and safety evaluation of the study drug;

[0213] (14) Clinical or laboratory evidence of human immunodeficiency virus (HIV) or syphilis carriage / infection.

[0214] If an enrolled subject becomes unsuitable for continuing the study during the study, the researcher may decide to withdraw the subject from the study, including:

[0215] (1) During the clinical trial, the subject develops certain comorbidities, complications, or worsens his / her condition, and the researcher determines that the subject is not suitable to continue the trial;

[0216] (2) Major protocol deviation: after randomization / administration, it is found that the subject does not meet the inclusion criteria of the study protocol, or the subject has poor compliance, does not follow the requirements of the study protocol or does not follow the doctor's advice, and uses other treatments without authorization, which affects the efficacy and safety assessment, or the researcher judges that continuing to participate in the study may cause unacceptable risks to the subject's health;

[0217] (3) The researcher believes that continuing treatment would be detrimental to the patient (e.g., pregnancy);

[0218] (4) The subject experiences an adverse event or a serious adverse event, and the investigator determines that the subject is not suitable to continue the trial;

[0219] (5) Lack of effectiveness. The investigator determines that the subject cannot benefit from the study treatment and that continued participation in the study would impose unacceptable risks on the subject;

[0220] (6) Other factors not mentioned above must be specified.

[0221] The subject is unwilling to continue to participate in the clinical study (according to the provisions of the informed consent form, the subject has the right to withdraw from the study at any stage of the study), including:

[0222] (1) Although the subject did not explicitly request to withdraw from the study, he or she no longer accepted the test and was lost to follow-up (or "dropped out");

[0223] (2) Unable to continue clinical research due to other reasons;

[0224] (3) Loss to follow-up due to unexplained reasons. Loss to follow-up is defined as the subject losing contact. Researchers should try to understand the reasons for withdrawal or dropout and record them. For example, they may find it difficult to tolerate certain adverse reactions.

[0225] For patients who terminate or withdraw from the study, the naltrexone implant or placebo should be removed. The investigator must indicate the reason for withdrawal on the case report form, contact the patient whenever possible, complete all assessment items, and complete the end-of-treatment follow-up record form, recording the time of the last follow-up visit whenever possible. For withdrawals due to adverse events, if the follow-up ultimately determines that they are related to the trial drug, this must be recorded on the case report form and the sponsor notified. Regardless of the reason for withdrawal, the case report form should be retained, and the final visit should be completed. The last test result should be used as the final result for a full data analysis of efficacy and adverse reactions. All study-related toxicities and SAEs present at the time of withdrawal must be followed up until they resolve, unless, in the investigator's opinion, the condition is unlikely to resolve due to the patient's underlying disease. Patients who withdraw from the study prematurely will not be replaced. For patients who withdraw prematurely from the study, if they continue to require alcohol abstinence treatment (referral or hospitalization), necessary medical support should be provided, and their safety should continue to be followed up. Subjects who withdraw from the study early but refuse to remove the naltrexone implant or placebo will be required to receive safety follow-up (telephone follow-up of adverse events and concomitant medication information) at each subsequent scheduled visit unless the subject explicitly indicates that they no longer want to receive any follow-up.

[0226] After signing the informed consent form and passing the inclusion / exclusion criteria screening, the subjects participating in the trial will be randomly assigned to receive either the drug treatment group (naltrexone or risperidone implant) or the blank group in a 2:1 ratio.

[0227] Subjects were randomly selected at a drug rehabilitation center between -28 and -1 days before dosing. On day 0, subjects were administered a naltrexone / risperidone implant (naltrexone:risperidone = 150 mg:15 mg). A control group received no medication. Follow-up was conducted weekly for up to 14 weeks after dosing.

[0228] 1. Efficacy indicators

[0229] 1.1 Main efficacy indicators

[0230] The primary efficacy outcome measure was the percentage of weeks free from cannabis use. Specifically, the number of drug-free weeks was determined by recording whether or not cannabis use occurred each week. "Drug-free weeks" were divided by "weeks at risk for drug use," with these days calculated until efficacy observation was discontinued. "Weeks at risk for drug use" were defined as the number of weeks in the study during which the subject was observed for efficacy. "Drug-free weeks" were defined as negative urine tests at weekly follow-up visits.

[0231] 1.2 Secondary efficacy indicators

[0232] Secondary efficacy measures included (1) time to patient dropout (calculated from the first dose); (2) Cannabis Craving Questionnaire (MCQ): craving scale scores from baseline to pre-specified weekly visits; (3) incidence of subjects with recurrent physical drug dependence during the 14-week treatment period; and (4) Brief Psychiatric Rating Scale: Brief Psychiatric Rating Scale from baseline to pre-specified weekly visits.

[0233] The patient dropout time (calculated from the first dose) refers to the time from randomization / dose to loss of follow-up / end of the trial.

[0234] The Marijuana Craving Questionnaire (MCQ) measures marijuana cravings weekly after randomization / administration. Items are rated on a Likert-type scale from 1 (strongly disagree) to 7 (strongly agree). Each participant's factor score is calculated by summing the three items from each factor scale, resulting in a score range of 3 to 21. The MCQ consists of four factors: 1) Compulsivity, which describes the inability to control marijuana use; 2) Emotionality, which describes marijuana use in the hope of relieving withdrawal or negative emotions; 3) Expectancy, which describes the anticipation of positive outcomes from marijuana use; and 4) Purpose, intention, and plan for using marijuana to achieve positive outcomes. The maximum score is 84 and the minimum score is 12, with higher scores indicating more severe craving symptoms endorsed by the participant.

[0235] The incidence of relapse of physical drug dependence during the 14-week treatment period refers to the proportion of patients who relapsed from randomization / dosing to loss to follow-up / end of the trial.

[0236] The Brief Psychiatric Rating Scale (BPRS) is a psychiatric rating scale that allows clinicians or researchers to measure patients' psychiatric symptoms, such as depression, anxiety, hallucinations, and other abnormal behaviors. It mainly assesses psychiatric symptoms and on-site conversations within the past week. It is a 7-point rating scale, which is assessed based on the intensity, frequency, duration, and degree of impact on related functions. (1) No symptoms; (2) Suspicious or very mild, there seem to be some signs, but the clinical significance is uncertain; (3) Mild, although the symptoms are mild, the clinical significance is certain; (4) Moderate; (5) Severe; (6) Severe; (7) Extremely severe. The total score (168 points) reflects the severity of the disease. The higher the total score, the more severe the disease. The change in the total score before and after treatment reflects the effectiveness of the treatment. The larger the difference, the better the effect. The general research inclusion standard can be set at >35 points.

[0237] 2. Safety Assessment Indicators

[0238] Adverse events (AEs) and serious adverse events (SAEs) (including local AEs and SAEs at the implant site), abnormal occurrence of vital signs before and after treatment, physical examination, 12-lead and above electrocardiogram, laboratory safety data (blood routine, urine routine, clinical biochemistry, coagulation routine) and other indicators.

[0239] 3. Trial Drugs

[0240] The test drug was the naltrexone-risperidone implant prepared in Example 1, with a specification of 150 mg: 15 mg / tablet;

[0241] The administration method and dosage are subcutaneous implantation in the abdomen, single administration.

[0242] During the 4-week screening period (Day-28 to Day-1), participants will undergo a screening visit (Visit 1), and qualified participants will be randomized on Visit 2 (D0). Participants enrolled in the trial group will receive the naltrexone risperidone implant. Subjects will undergo a single subcutaneous abdominal incision implant on the day of randomization (D0, Visit 2). The control group will not receive any medication. Follow-up after randomization / dosing will last until Week 14, with patients returning to the research center for a visit once a week. A total of 15 follow-up visits will be conducted.

[0243] Sample size calculation: Assuming that the relapse rate decreases by 20% after medication use, that is, after 14 weeks, the natural adherence rate is 40%, and the adherence rate in the experimental group is 70%. Based on statistical calculations, a sample size of 100 cases meets statistical requirements.

[0244] The analysis set is calculated as follows:

[0245] Randomized analysis set: Based on the intention-to-treat (ITT) principle, including all randomized subjects;

[0246] Per-protocol analysis set (PPS): includes all subjects in the randomized analysis set who have completed 14 weeks of follow-up after randomization / dosing and have no major protocol violations. As a subset of the randomized analysis set, it will be marked in the randomized analysis set;

[0247] Safety analysis set (SS): includes all subjects who were randomly enrolled, received study drug treatment, and underwent at least one safety assessment;

[0248] Among them, the analysis of demographics and baseline characteristics uses the randomized analysis set, the efficacy analysis uses the randomized analysis set, the PPS analysis can provide supplementary evidence, and the safety analysis is based on the safety analysis set.

[0249] Efficacy analysis method: The efficacy analysis is based on the randomized analysis set, and the efficacy analysis results based on PPS can provide supplementary evidence.

[0250] Safety analysis method: Safety was analyzed based on SS. Adverse events were coded using the terms of the Medical Dictionary for Reproductive Systems (MedDRA) (the latest version at the time of analysis), and descriptive statistical analysis was performed according to the system organ class (SOC) / preferred term (PT). The overall incidence of adverse events, adverse reactions (i.e., adverse events whose relevance was not "definitely unrelated"), adverse events occurring during treatment, important adverse events, and serious adverse events were calculated, as well as the incidence rates distinguished by SOC / PT. The number and frequency of adverse events and adverse reactions occurring during treatment were counted by SOC / PT and severity. A detailed list of adverse events, adverse reactions, adverse events occurring during treatment, important adverse events, and serious adverse events was prepared.

[0251] For laboratory tests, a cross-tabulation of normal / abnormal results before and after medication is used to illustrate the changes in results before and after medication. A detailed list of laboratory test results is provided.

[0252] For electrocardiograms, a cross-tabulation of normal / abnormal values ​​before and after medication was used to illustrate changes in results. QTc interval measurements were statistically described as >450ms, >480ms, >500ms, and increases of >30ms and >60ms from baseline.

[0253] Make a detailed list of the electrocardiogram results and liver and gallbladder ultrasound results.

[0254] Analyze and tabulate the results of each visit's vital signs and physical examination indicators. See General Principles for analysis methods.

[0255] The trial flow chart is shown in Figure 1. In Figure 1, patients were required to sign an informed consent form before commencing any study-related procedures. Demographic information included sex, age, ethnicity, height, weight, body mass index, history of allergies, drug abuse, smoking, alcohol abuse, and blood donation. Vital signs included temperature (forehead), seated blood pressure, heart rate, and respiratory rate. Seated blood pressure and heart rate were measured after 5 minutes of rest. A comprehensive physical examination, organized by organ and system, included the following: general appearance, head and neck, lymph nodes, skin, chest, abdomen, musculoskeletal system (including limbs and spine), and nervous system. Fasting blood and urine samples for laboratory testing should be collected on the morning of the visit before randomization / dose administration. This included urine and / or blood samples for serum pregnancy testing in women of childbearing potential.

[0256] Laboratory tests included: 1) complete blood count: including hemoglobin (Hb), hematocrit (HCT), mean corpuscular volume (MCV), red blood cell count (RBC), white blood cell count (WBC), differential white blood cell count (including neutrophils, lymphocytes, monocytes, basophils, and eosinophils), and platelets (PLT);

[0257] 2) Urinalysis: including pH, urine protein (U-PRO), urine white blood cells (U-WBC), urine red blood cells (U-RBC), urine glucose (U-GLU), urine occult blood, and urine ketone bodies (U-KET);

[0258] 3) Serum biochemistry: including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-glutamyl transferase (GGT), total bilirubin (TBIL), direct bilirubin (DBIL), albumin (ALB), total protein (TP), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C); serum creatinine (sCr), urea (Urea) or urea nitrogen (BUN), uric acid (UA), potassium (K), sodium (Na), chloride (Cl), calcium (Ca), phosphorus (P), magnesium (Mg), and blood glucose (GLU);

[0259] 4) Pregnancy Test (Females of Childbearing Age Only): Serum pregnancy tests are only performed during the Screening Period and Visit 9. Serum pregnancy tests for females of childbearing age must be negative. Urine pregnancy tests may be performed as needed during the study treatment. If the urine pregnancy result is positive, a serum pregnancy test is required for confirmation. If confirmed positive, the subject must withdraw from the study and the investigator will continue to follow up the subject until the end of the pregnancy.

[0260] 5) Serological virological examination: including human immunodeficiency virus (HIV) antibodies, hepatitis C virus (HCV) antibodies, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis B virus (HBV) deoxyribonucleic acid (DNA), HCV-ribonucleic acid (RNA), and syphilis-specific antibodies (Anti-TP). Serological virological examination is only performed during the screening period;

[0261] 6) Coagulation function: including prothrombin time (PT), prothrombin time international normalized ratio (INR, performed only during the screening period), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB);

[0262] 7) Electrocardiogram with 12 or more leads: including heart rate, ventricular rate, PR interval, QT / QTc interval, and QRS complex morphology after at least 5 minutes in the supine position.

[0263] 8) Hepatobiliary B-ultrasound: Before randomization / drug administration, the test was performed on the morning of the visit when the subject was fasting, and was only performed at Visit 1 and Visit 14;

[0264] 9) Naltrexone-risperidone implants are implanted subcutaneously in the abdomen. Patients are hospitalized for 2 hours after administration. The wound dressing is changed by the patient on the third day after surgery.

[0265] 10) For subjects who withdraw from the study early, an exit visit is required within 2 weeks after confirmation of withdrawal from the study. The content of the visit is the same as the end-of-study visit.

[0266] The research results of this example show that the naltrexone-risperidone implant can effectively reduce the relapse rate of patients. At the visits in week 4 and thereafter, the positive rate of urine test results of patients was lower than that of the placebo group, indicating that the naltrexone-risperidone implant can effectively prevent the relapse of marijuana addicts. The results of the marijuana craving questionnaire show that the naltrexone-risperidone implant can significantly reduce the patients' craving for marijuana. The results of the Brief Psychiatric Rating Scale (BPRS) show that the naltrexone-risperidone implant can significantly improve the mental symptoms of marijuana addicts, especially the anxiety, depression, hallucinations and other mental symptoms caused by marijuana addiction.

[0267] All documents mentioned in this application are cited as references in this application, just as each document is cited as reference separately. Unless they conflict with the application purpose and / or technical solution of this application, the cited documents involved in this application are cited in their entirety and for all purposes. When cited documents are involved in this application, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When cited documents are involved in this application, the examples and preferred embodiments of the cited relevant technical features may also be incorporated into this application as references, but are limited to the ability to implement this application. It should be understood that when the cited content conflicts with the description in this application, the present application shall prevail or be adaptively amended according to the description in this application.

[0268] The various technical features of the above-mentioned implementation modes and examples can be combined in any appropriate manner. In order to make the description concise, not all possible combinations of the various technical features in the above-mentioned implementation modes and examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of the description in this specification.

[0269] The embodiments described above only express several implementation methods of the present application, but they should not be understood as limiting the scope of the patent application. It should be pointed out that, for those of ordinary skill in the art, without departing from the concept of the present application, several variations and improvements can be made, which all fall within the scope of protection of the present application. In addition, it should be understood that after reading the above-mentioned teaching content of the present application, those skilled in the art can make various changes or modifications to the present application, and the equivalent forms obtained also fall within the scope of protection of the present application. It should also be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided in the present application are all within the scope of protection of the claims attached to the present application. Therefore, the scope of protection of the patent application of the present application shall be based on the attached claims, and the description can be used to interpret the content of the claims.

Claims

1. A pharmaceutical composition for preventing relapse of marijuana addiction, wherein the active pharmaceutical ingredients of the pharmaceutical composition include naltrexone and risperidone.

2. The pharmaceutical composition according to claim 1, It is characterized in that The mass ratio of the naltrexone to the risperidone is (5-30):

1.

3. The pharmaceutical composition according to claim 2, It is characterized in that The mass ratio of the naltrexone to the risperidone is (8-15):

1.

4. The pharmaceutical composition according to any one of claims 1 to 3, It is characterized in that Also included are pharmaceutically acceptable carriers.

5. The pharmaceutical composition according to any one of claims 1 to 4, It is characterized in that The drug is prepared together with pharmaceutically acceptable adjuvants into clinically acceptable preparations.

6. The pharmaceutical composition according to claim 5, It is characterized in that The preparation is selected from any of the following groups or a suitable combination thereof: 1) Tablets, capsules, granules, powders, granules, suspensions or solutions; 2) Oral solution, lozenge, injection, suppository, spray, drops or patch.

7. The pharmaceutical composition according to claim 6, It is characterized in that The preparation is in the form of an implant.

8. The pharmaceutical composition according to any one of claims 1 to 7, It is characterized in that The subject is a mammal.

9. The pharmaceutical composition according to claim 8, It is characterized in that The subject is a human or a rat.

10. Use of the pharmaceutical composition according to any one of claims 1 to 9 in the preparation of a drug for preventing relapse of marijuana addiction.

11. Use of the pharmaceutical composition according to any one of claims 1 to 9 in the preparation of a drug for treating adverse symptoms caused by cannabis addiction.

12. The use according to claim 11, It is characterized in that The adverse symptoms caused by marijuana addiction include psychotic symptoms.

13. The use according to claim 12, It is characterized in that The psychiatric symptoms include anxiety, depression and hallucinations.

14. A method for preventing relapse of marijuana addiction, comprising administering a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 9 to a patient in need thereof.

15. A method for treating adverse symptoms caused by cannabis addiction, comprising administering a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 9 to a patient in need thereof.

16. The method according to claim 15, It is characterized in that The adverse symptoms caused by marijuana addiction include psychotic symptoms.

17. The method according to claim 16, It is characterized in that The psychiatric symptoms include anxiety, depression and hallucinations.

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